Causal relationship between dyslipidemia and risk of facial aging: Insights from Mendelian randomization in East Asian populations

Abstract Background Emerging observational studies showed an association between dyslipidemia and aging. However, it remains unclear whether this association is causal, particularly in the case of Asians, which are aging more rapidly than other continents. Given the visible manifestations of aging often include changes in facial appearance, the objective of this study is to assess the causal relationship between dyslipidemia and facial aging in East Asian populations. Methods SNPs related to dyslipidemia in East Asian people such as Total cholesterol (TC), High‐density‐lipoprotein cholesterol (HDL), Low‐density‐lipoprotein cholesterol (LDL), and Triglyceride (TG) along with outcomes data on facial aging, were extracted from public genome‐wide association studies (GWAS). A two‐sample Mendelian randomization (MR) analysis was then performed using publicly available GWAS data to investigate the potential causal relationship. The effect estimates were primarily calculated using the fixed‐effects inverse variance weighted (IVW) method. Results Totally, 88 SNPs related to HDL among 70657 East Asian participants in GWAS. Based on the primary causal effects model using MR analyses with the IVW method, high HDL level was demonstrated as significantly related to the risk of facial aging (OR, 1.060; 95% CI, 1.005–1.119, p = 0.034), while high TC level (OR, 0.995; 95% CI, 0.920–1.076, p = 0.903), high LDL level (OR, 0.980, 95% CI, 0.924–1.041, p = 0.515), as well as high TG level (OR, 0.999, 95% CI, 0.932–1.071, p = 0.974), showed no significant correlation with facial aging. Conclusions The two‐sample MR analysis conducted in this study revealed a positive causal relationship between high HDL levels and facial aging. In contrast, facial aging demonstrated no significant correlation with high levels of TC, LDL, or TG. Further large‐sample prospective studies are needed to validate these findings and to provide appropriate recommendations regarding nutrition management to delay the aging process among old patients in East Asia.


INTRODUCTION
Dyslipidemia, characterized by abnormal lipid levels in the bloodstream, is commonly associated with various cardiovascular risks. 1 However, its relationship with facial aging, a complex process influenced by both genetic and environmental factors, is not as straightforward.Facial aging involves changes in skin elasticity, wrinkle formation, and collagen degradation. 2Studies have suggested that dyslipidemia may exacerbate these aging processes due to the impact of lipids on skin integrity and inflammation. 3Conversely, other research points to a lack of direct correlation between dyslipidemia and accelerated facial aging, indicating that factors such as UV exposure and lifestyle choices play a more significant role. 4,5Thus, the current understanding of the link between dyslipidemia and facial aging is inconclusive and marked by contradictions.Further investigation is needed to clarify this relationship, considering the potential influence of other variables such as dietary habits and genetic predisposition, to develop a more comprehensive understanding of how dyslipidemia might affect facial aging.
Mendelian randomization (MR) has emerged as a prominent method for examining the potential causative links between various exposures and health outcomes. 6Differing from traditional observational research, MR analysis uniquely counters reverse causation bias, given that the random allocation of alleles happens prior to the development of diseases.This methodology leverages the random distribution and independent assortment of genetic variations at the time of conception.By employing genetic markers as instrumental variables (IVs), MR effectively reduces the impact of confounders. 7,8The widespread availability of comprehensive genome-wide association studies (GWASs) enhances the capacity for causal investigations.Utilizing MR analysis, this study seeks to unravel a critical inquiry: What is the nature of the relationship between Dyslipidemia and Facial aging-is it negative, neutral, or positive?as TC, HDL, LDL, and TCG. 9

Data sources
The study conducted a comprehensive analysis using open-access, summary-level data from GWASs, which predominantly targeted traits in East Asian populations, including both genders.1).Given that all GWAS datasets used in this analysis are readily accessible and have received prior approval from respective ethical review boards, obtaining fresh ethics approval for this study was deemed unnecessary.

Selection and validation of SNPs
To select suitable SNPs, three distinct criteria were applied.First, SNPs linked to TC, HDL, LDL, and TCG were pinpointed, meeting the genome-wide significance threshold (p < 1 × 10 -5 ).Next, the independence of these SNPs was ascertained by analyzing pairwise-linkage disequilibrium. 10Any SNP with an r2 greater than 0.001, within a deemed strong enough to minimize potential bias. 11Prior to initiating the MR analysis, we conducted data-harmonization procedures to ensure that the effects attributed to an SNP on both the exposure and the outcome were aligned with the same allele.

MR analysis
The main analysis incorporated an inverse-variance weighted (IVW) meta-analysis utilizing a fixed-effects approach.To examine pleiotropy, the MR-PRESSO method was employed, aiding in the assessment of horizontal pleiotropy in the chosen IVs. 12 Cochrane's Q-value served as the metric for gauging heterogeneity among these IVs.Additionally, a leave-one-out sensitivity analysis was executed to determine the influence of individual SNPs on the aggregate results.All statistical evaluations were carried out using the "TwoSampleMR" package within R version 4.0.3, as provided by the R Foundation for Statistical Computing in Vienna, Austria.

SNP selection and validation
To summarize, the research incorporated in our analysis was conducted between 2019 and 2020, with a primary emphasis on the East Asian demographic (referenced in Table 1).Each of the chosen IVs achieved genome-wide significance, and all exhibited F-statistics exceeding ten (as detailed in Table 2).

HDL and facial aging
In the primary analysis of causal effects using MR with the IVW method, a notable correlation was observed between elevated HDL levels and the risk of Facial aging (OR, 1.060; 95% CI, 1.005-1.119;p = 0.034, as seen in Figure 2).However, alternative methods like MR-Egger (OR, 1.041; 95% CI, 0.949-1.141;p = 0.401) and weighted median (OR, 1.023; 95% CI, 0.937-1.118;p = 0.611) did not establish a statistically significant link between HDL levels and Facial aging, yet their effect direction was consistent with the IVW method.The absence of potential heterogeneity was confirmed through heterogeneity analysis (p = 0.880, Table 3), enhancing the credibility of the IVW findings.Additionally, the MR results showed no signs of horizontal pleiotropy (p = 0.877).Both the forest plot and scatter plot, depicted in Figure 3 and Figure 4 respectively, underscored the consistency of these results.The leave-one-out sensitivity analysis, illustrated in Figure S1, verified that no single SNP disproportionately impacted the overall estimates.

F I G U R E 2
The relationships between genetically predicted levels of total cholesterol, HDL, LDL, and Triglyceride, and their effects on facial aging.CI, confidence interval; HDL, high density lipoprotein; LDL, low density lipoprotein; OR, odds ratio.

TA B L E 3
The result of heterogeneity and pleiotropy test.

Triglyceride and facial aging
The MR analyses consistently demonstrated that TCG did not exhibit a significant genetic association with Facial aging, as evidenced by the following results: OR of 0.999 (95% CI, 0.932-1.071;p = 0.974) for IVW, OR of 1.043 (95% CI, 0.935-1.164;p = 0.453) for MR Egger, and OR of 0.982 (95% CI, 0.878-1.098;p = 0.748) for the weighted median approach (Figure 2).Furthermore, these analyses found no indications of heterogeneity (p = 0.871) or horizontal pleiotropy (p = 0.882), as detailed in Table 3.The leave-oneout sensitivity analysis, illustrated in Figure S1, confirmed that the aggregate results were not disproportionately affected by any single SNP.

DISCUSSION
In recent aging research, the influence of dyslipidemia, defined by irregular levels of lipids in the blood, on facial aging has become a topic of significant interest. 13While prior research has examined this link, findings have been mixed, with some studies not finding a definitive connection between dyslipidemia and the aging of facial features. 4 light of this, our study focuses on dyslipidemia as a key element, utilizing MR to delve into its association with facial aging.The MR approach allows for the assessment of a cause-and-effect relationship between dyslipidemia and facial aging, using genetic variations as IVs, which helps to reduce the bias usually seen in observational studies. 14is study represents the inaugural use of MR to investigate the causal impact of dyslipidemia on facial aging.Utilizing a two-sample MR approach, we conducted an extensive analysis to understand the causal Overabundance of antioxidants could disrupt this balance, potentially affecting skin aging. 16(2) Influence on Skin Lipids: HDL plays a role in lipid metabolism.Changes in the lipid composition of the skin can influence skin barrier function and hydration, which are critical in maintaining youthful skin.Excessive or altered HDL levels might disrupt the normal lipid balance in the skin, leading to changes associated with aging. 17(3) Impact on Hormonal Balance: Lipoproteins can influence hormonal levels and metabolism.Hormones like estrogen have a known impact on skin health and aging.
Elevated HDL might indirectly affect facial aging through hormonal pathways. 18(4) Modulation of Inflammation: Although HDL is typically anti-inflammatory, the role of inflammation in aging (including skin aging) is complex.It's possible that changes in inflammatory responses due to altered HDL levels could accelerate aging processes in the skin. 19r study confirmed a causal relationship between the elevated HDL levels and the acceleration of facial aging, which has important This study presents various strengths and limitations.Its primary strength is the use of MR analysis, which minimizes biases related to residual confounding and reverse causation.This approach significantly bolsters the thorough investigation of the HDL-facial aging relationship.However, several constraints need acknowledgment.Firstly, completely ruling out the impact of directional pleiotropy in MR studies is inherently difficult.Nonetheless, our MR-PRESSO assessments found no pleiotropic effects, and our sensitivity analyses yielded consistent findings.Secondly, the GWASs we reviewed primarily involved East Asian individuals, which may limit the applicability of our results to other ethnic groups.Lastly, the lack of detailed data on the types of HDL restricted our ability to explore variations in the association with HDL levels based on these specific characteristics.
This two-sample MR analysis found a causally positive association between HDL level and facial aging, suggesting that higher levels of HDL, commonly known as "good cholesterol," might be linked to increased signs of aging in the face.The implications of this finding are multifaceted, as HDL is typically associated with various health benefits, particularly in terms of cardiovascular health.However, this research introduces a novel perspective by possibly linking it to an aging or dermatological outcome.

CONFLICT OF INTEREST STATEMENT
No disclosures were reported.

Figure 1
Figure 1 depicts the research methodology, highlighting MR's three core hypotheses: (A) Significant correlation between single nucleotide polymorphisms (SNPs) and lipid profiles, including Total cholesterol (TC), High-density-lipoprotein cholesterol (HDL), Low-densitylipoprotein cholesterol (LDL), and Triglycerides (TCG); (B) SNPs' autonomy from established confounding variables; and (C) The exclusive influence of SNPs on Facial aging is channeled through lipid levels such

F I G U R E 3 F I G U R E 4
Forest plot of the association of HDL and Facial aging.HDL, high density lipoprotein.Scatter plot of the association of HDL and Facial aging.HDL, high density lipoprotein.
links between various lipid profiles-TC, HDL, LDL, and TCG-and the aging of facial features.Our findings indicate a casual correlation where elevated HDL levels could contribute to an increased risk of facial aging.This aligns with the observations made by Johanna et al.in 2019, who also noted a heightened risk of age-related diseases in individuals with higher HDL levels.15Notably, our MR methodology provides more robust conclusions than prior observational studies, given its resistance to confounding variables and avoidance of reverse causality.There are several possible mechanisms that could explain the causal relationship between the elevated HDL levels and the development of facial aging: (1) Antioxidant Effects: HDL has antioxidant properties.While this is generally positive, a high level of antioxidants might interfere with certain cellular processes.In skin aging, the balance between oxidative stress and antioxidant defense is crucial.
implications for clinical practice and prevention strategies.The following are possible clinical applications: (1) Preventive Healthcare: Patients with naturally high HDL levels or those taking medication to increase HDL might be monitored more closely for signs of accelerated facial aging.This could lead to early intervention strategies.(2) Aesthetic and Dermatological Treatments: This knowledge can guide dermatologists and cosmetic surgeons in advising patients who are concerned about facial aging.For those with elevated HDL levels, specific anti-aging treatments could be recommended.(3) Nutritional Advice: Since HDL levels can be influenced by diet, nutritionists could use this information to give advice that balances cardiovascular benefits with potential impacts on facial aging.
The characteristics of GWAS data.
The fundamental assumptions of the Mendelian randomization study: (A) Single-nucleotide polymorphisms (SNPs) have a strong association with TC, HDL, LDL, and TG; (B) SNPs are not influenced by confounding factors; (C) SNPs impact facial aging exclusively through TC, HDL, LDL, and TG.TC, Total cholesterol; HDL, high density lipoprotein; LDL, low density lipoprotein; TG, Triglyceride.

Table 3 .
Single nucleotide polymorphisms used as instrumental variables in the Mendelian randomization analyses of HDL.
Sensitivity analyses, illustrated in FiguresS1 and S2, further corroborated that the collective estimates were not significantly skewed by any individual SNP.TA B L E 2Abbreviations: Chr, chromosome; EA, effect allele; HDL, high density lipoprotein; NEA, non-effect allele; SE, standard error; SNP, single nucleotide polymorphisms.